Genetic mapping and genome-wide studies provide evidence for the association of several genetic polymorphisms with malaria, a complex pathological disease with multiple severity degrees. We have previously described Berr1and Berr2as candidate genes identified in the WLA/Pas inbreed mouse strain predisposing to resistance to cerebral malaria (CM) induced by P. bergheiANKA. We report in this study the phenotypic and functional characteristics of a congenic strain we have derived for Berr2WLAallele on the C57BL/6JR (B6) background. B6.WLA-Berr2was found highly resistant to CM compared to C57BL/6JR susceptible mice. The mechanisms associated with CM resistance were analyzed by combining genotype, transcriptomic and immune response studies. We found that B6.WLA-Berr2mice showed a reduced parasite sequestration and blood–brain barrier disruption with low CXCR3+T cell infiltration in the brain along with altered glial cell response upon P. berghei ANKAinfection compared to B6. In addition, we have identified the CD300f, belonging to a family of Ig-like encoding genes, as a potential candidate associated with CM resistance. Microglia cells isolated from the brain of infected B6.WLA-Berr2mice significantly expressed higher level of CD300f compared to CMSmice and were associated with inhibition of inflammatory response.